Derivatives of 1,4-dihydro-3h-2,3-benzoxazine

ABSTRACT

1,6-Dihydro-4-phenyl-2,5,3-benzodioxazocine (1), 1,4-dihydro-3H2,3-benzoxazine-3-carboxamide (1&#39;&#39;a), N-alkyl-1,4-dihydro-3H-2,3benzoxazine-3-carboxamides (1&#39;&#39;b), 1,4-dihydro-3H-2,3-benzoxazine3-carboxamidine (1&#39;&#39;c) and its acid addition salts, process for the preparation thereof and novel intermediates prepared by said processes. Compounds 1, 1&#39;&#39;a, and 1&#39;&#39;b principally exhibit antilipemic activity. Compound 1&#39;&#39;c is useful for preparing mothproofing agents and inhibitors that can be used in the acid pickling of steel.

United States Patent [72] lnventor David G. Martin Kalamazoo, Mich.

[21] Appl. No. 686,733

[22] Filed Nov. 29, 1967 [45] Patented Dec. 7, 1971 [73] Assignee The Upjohn Company Kalamazoo, Mich.

[54] DERIVATIVES OF 1,4-DlllYDRO-3H-L3- BENZOXAZINE 6 Claims, No Drawings [52] U.S. Cl 260/244 R,

260/333, 260/453 AR, 424/248 [51] Int. Cl C0711 87/12 [50] Field of Search 260/244 [56] References Cited UNITED STATES PATENTS 2,661,272 12/1953 Searle 260/553 OTHER REFERENCES Migrdichian Organic Synthesis Vol. 1, page 448 N. Y., Reinhold, 1957 QD262.M55

Pifferi et al., Gazzetta Chimica ltaliana Vol. 96, pages 1,671- 1,695 (1966, Dec.) QDl.G28.

Pifferi et al., Chem. Abst. Vol. 67, No. 43766e (1967) QDLASI.

Wagner et al., Synthetic Organic Chemistry page 645 N. Y., Wiley, 1953 QD262.W24.

Primary Examiner-Natalie Trousof Attorneys-Eugene O. Retter and John Kekich ABSTRACT: l,6-Dihydro-4-phenyl-2,5,B-benzodioxazocine 1 1,4-dihydro31-1-2,3-benzoxazine-3-carboxamide 1 'a), N-alkyll ,4-dihydro-3l-l-2,3-benzoxazine-3-carboxamides 1 'b), 1,4-dihydro-3H-2,3-benzoxazine-3-carboxamidine (l'c) and its acid addition salts, process for the preparation thereof and novel intermediates prepared by said processes. Compounds 1, 1'0, and lb principally exhibit antilipemic activity. Compound l'c is useful for preparing mothproofing agents and inhibitors that can be used in the acid pickling of steel.

DERIVATIVES OF l,4-DIIIYDRO-3H-2,3-BENZOXAZINE BRIEF SUMMARY OF THE INVENTION This invention relates to novel compounds and processes for preparing the same. More particularly this invention relates to I,6'dyhydro-4-pheny|-2,5,S-benzodioxazocine having the formula:

wherein R is alkyl having from one to four carbon atoms, inclusive.

DETAILED DESCRIPTION and l,4-dihydro-3H-2,3-benzoxazine derivatives having the formula:

wherein X is selected from the group consisting of l,4-dihydro-3H-2,3-benzoxazine hydrochloride in accordance with the following equations:

KCNVX wherein R is alkyl containing from one to four carbon atoms,

inclusive.

The alkyl esters of l,4-dihydro-3ll-I-2,3-benzoxazine-3-carboxylic acid, Formula IV, are prepared by reacting ortho-( bischloromethyl)benzene with an alkyl hydroxycarbamate. The process is illustrated in the reaction designated above as reaction E. The reaction is conducted in the presence of a base and an inert solvent, for example, methanol, ethanol, isopropanol, and the like. The alkali-metal alkoxides, illustratively sodium ethoxide and sodium isopropoxide, are the preferred bases. The reactant ratios can vary over a wide range; however, the preferred ratio is one mole of ortho-( bischloromethyl)benzene, one mole of the carbamate, and two moles of the base. It has been found that this ratio reduces the occurrence of side reactions. The reaction is preferably conducted under reflux conditions to insure that the reaction proceeds at a reasonable rate and that the formation of byproducts is minimized; however, lower temperatures may be used if desired.

Separation of the product from the reaction mixture is easily accomplished by the conventional separation techniques such as evaporation, filtration and distillation.

The compound 3-benzoyll ,4-dihydro-3H-2,3-benzoxazine (formula V) can be prepared by any of three methods. In the first method, it is prepared by reacting ortho-(bischloromethyl)-benzene with benzohydroxamic acid in the presence of a base and inert solvent, for example, methanol, ethanol, isopropanol, and the like. The base is preferably an alkali-metal alkoxide, illustratively sodium ethoxide or sodium isopropoxide. The process is illustrated by the following equation:

OH H l wherein R is alkyl containing from one to four carbon atoms, inclusive, and M is a metal cation, preferably an alkali-metal cation. The preferred base for this reaction is sodium isopropoxide. The quantities of reactants used are one mole of the ortho-(bis-chloromethyl)benzene, one mole of the benzohydroxamic acid and two moles of base. A wide range of temperatures may be used, but it is preferred to operate under reflux conditions to reduce the occurrence of side reactions. In addition to 3-benzoyl-l ,4-dihydro-3H-2,3-benzoxazine, this reaction yields 0-[o-(alkoxymethyl)benzyl]benzohydroxamic acid, formula VI, and other byproducts containing the group. The desired product can be separated from byproducts either by chromatographic or extraction procedures.

The second method for preparing 3-benzoyl-l,4-dihydro-3 H-2,3-benzoxazine involves the reaction of one mole of ortho- (bis-chloromethyl)benzene with two moles of the alkali-metal salt of benzohydroxamic acid. This process is illustrated by the following equation:

wherein R is alkyl containing from one to four carbon atoms,

inclusive, and M is a metal cation, preferably an alkali-metal cation. The reaction is most advantageously conducted under reflux conditions in the presence of an inert solvent, for exam- 5 ple, methanol, ethanol, isopropanol, or the like. Byproducts formed in this reaction have structures illustrated by formulas VII and VIII.

A third method for preparing 3-benzoyl-l ,4-dihydro-3H- 2,3-benzoxazine involves the reaction of equimolar quantities of an alkali-metal benzohydroxamate, a base and ortho-( bischloromethyl)benzene. This reaction is most advantageously carried out by slowly adding an aqueous solution of the alkalimetal benzohydroxamate and base to a refluxing alcoholic solution (e.g. methanol, ethanol, isopropanol, and the like) of the ortho-(bis-chloromethyl)benzene. This method is illustrated by the following equation:

011,01 i-NHOM' MOH CH Cl N 1 ll 0 0 wherein M is an alkali-metal cation. In addition to the 3- benzoyl-l,4-dihydro-3H-2,3-benzoxazine, this method yields the compound l,6-dihydro-4-phenyl-2,5,3-benzodioxazocine (formula I). The l,6-dihydro-4-phenyl-2,5,3-benzodioxazocine has exhibited antilipemic activity in animals.

The l,4-dihydro-3H-2,3-benzoxazine hydrochloride (formula ll) is obtained by reacting either the compound of formula IV or the compound of formula V with an anhydrous or aqueous solution of hydrogen chloride in an alkanol, as illustrated in reactions G and H. Suitable alkanols include methanol, ethanol, propanol, isopropanol, and the like. While the reaction is operable over a wide range of temperatures, e.g. 25 to 100 C., it is preferred to operate under reflux conditions to insure that the reaction proceeds at a reasonable rate and side reactions are minimized.

The details of the process for making the novel l,4-dihydro- 3H-2,3-benzoxazine derivatives of formula I will vary depending on whether compound l'a, Ib, or I'c is being prepared.

The compound, l,4-dihydro-3H-Z,3-benzoxazine-3-carboxamide (Va) is prepared by reacting an aqueous solution of 1,4- dihydro-3H-2,3-benzoxazine hydrochloride (II) with a metal cyanate as illustrated in reaction A. Although other metal cyanates can be used in this step, the alkali-metal cyanates are preferred because of their water solubility. Since the hydrochloride salt is also water soluble, the reaction readily takes place in an aqueous medium. This is advantageous because it eliminates (1) the step of converting the hydrochloride to its free base and (2) the need for utilizing some other solvent. While the reaction readily takes place at room temperature, it can be conducted over a wide range of temperatures, for example, to 100 C. The reactant ratios can vary over a wide range, but the best results are obtained when an excess of alkali cyanate is used.

The N-alkyl-l ,4-dihydro-3H-2,3-benzoxazine-3-carboxamides (I'b) can be prepared by converting l,4-dihydro-3l-l-2,3 -benzoxazine hydrochloride to its free base (Ill) by reacting an aqueous solution of the hydrochloride with a base, for example, an alkali-metal hydroxide, extracting the base with a solvent, e.g., ether, and then reacting the solution of free base with an alkyl isocyanate illustrated in reaction D.

The reaction between the alkyl isocyanate and the free base readily takes place at room temperature, but is can be conducted at temperatures below or above room temperatures, if desired. A wide range of reactant ratios can also be utilized but an excess of alkyl isocyanate is preferred. The reaction is advantageously carried out in an inert solvent, for example, diethyl ether, diisopropyl ether, benzene, toluene, methylene, chloride, ethyl acetate, and the like. The product can be recovered by conventional recovery techniques, for example, evaporation and crystallization.

The compound 1,4-dihydro 3I-l-2,3-benzoxazine-3-carboxamidine hydrochloride (I'c is prepared by reacting 1,4- dihydro-3H-2,3-benzoxazine hydrochloride (II) with cyanamide, as is shown in reaction C. The reaction is advantageously conducted in the presence of an inert solvent, for example, benzene, toluene, xylene, etc. Although lower temperatures can be utilized, the reaction is preferably con ducted under reflux conditions. Equimolar quantities of reactants or a slight excess of the cyanamide should be utilized. The product can be recovered from the reaction mixture by conventional recovery techniques.

It has been found that the novel compounds of this invention, represented by formulas I, l'a, lb, II, III, and IV, are useful in the treatment of hyperlipemic states in animals. For example, they lower serum cholesterol and triglycerides. The compounds were administered orally to Sprague-Dawley male rats in dosages of 5 mg/kg. and higher. For example, at a dosage of mg./kg., compound l'a reduced cholesterol and triglycerides 24 percent and 39 percent, respectively.

The compounds of formulas l'a and H2 exhibit sedative activity in animals. For example, the compound of formula l'a when administered to Rockland all-purpose albino mice, induces depression at dosages of 100 to 300 mgjkg. The L0,, is 562 mg./kg. The compounds of formula l'b also exhibit antiinflammatory activity.

The compound of formula I is an effective insecticide for crickets at a concentration of 0.2 percent.

The compounds of formulas I and V have exhibited antifungal activity, for example, against Blastomyces dermatitidis and Coccidioides immitis.

For purposes of administration to mammals, including animals of economic value, such as horses, cattle, sheep, pigs, mice, rats, rabbits, and the like, the compounds can be com bined with solid or liquid pharmaceutical carriers and formulated in the form of tablets, powder packets, capsules, and the like solid dosage forms, using starch and like excipients, or dissolved or suspended in suitable solvents or vehicles, for oral or parenteral administration.

The novel compound of formula I'c is a good vehicle for toxic acids. For example, the fluosilicic acid addition salt is useful as a mothproofing agent according to US. Pat. No. 2,205,789.

In addition, the compound of formula I'c can be converted to the thiocyanic acid addition salt and condensed with formaldehyde to form resins which are useful as inhibitors according to US. Pat. Nos. 2,425,320 and 2,606,155 in the acid pickling of steel.

The following examples are set forth to illustrate the products and processes of the present invention and are not intended to limit the scope thereof.

EXAMPLE 1 N-Methyl- 1 ,4-dihydro-3I-I-2,3-benzoxazine-3-carboxamide A. l,4-Dihydro-3I-ll-2,3-benzoxazine-3-carboxylic acid ethyl ester Sodium hydride (55 g. of 55 percent sodium hydride mineral oil dispersion; 1.25 moles) was cautiously dissolved in 1 ll. of absolute ethanol with stirring and cooling under an atmosphere of nitrogen. Ethyl hydroxycarbamate (64.2 g., 0.61 mole) was added to the cold sodium ethoxide solution. The resulting solution was kept in the ice bath while ml. portions of it were added slowly through a dropping funnel to a stirred, refluxing solution of 108.2 g. (0.62 mole) of ortho- (bis-chloromethyl)benzene in 1 ll. of ethanol. The addition required about 2 hrs., after which the reaction mixture was refluxed for an additional 1.75 hrs. After stirring overnight at room temperature, salts were removed by filtration and washed with ethanol. The filtrate was: evaporated to dryness under reduced pressure, and the residue taken up in ether, washed with water, 5 percent potassium hydroxide, water, 5 percent hydrochloric acid, and water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue consisted of two layers; the upper layer was essen' tially pure mineral oil and was siphoned off. The lower layer was distilled under reduced pressure (0.5 mm. Hg). Initially a forerun (15.52 g.) distilling 6585 C. was collected and discarded. This was followed by a fraction (3.21 g.) distilling 85l lObL C. which was a mixture of nonnitrogeneous material and l,4-dihydro-3lH-2,3-benzoxazine-3-carboxylic acid ethyl ester. This in turn was followed by l,4-dihydro-3l-I-2,3- benzoxazine-3-carboxylic acid ethyl ester (52.35 g.) distilling ll2-119 C. Spectra (IR, UV, NMR) were consistent with the structure.

AnaLCalcd. for C H,,NO,: C, 63.75, H, 6.32; N, 6.76.

Found: c, 63.70;", 6.33; N, 6.54.

The 1,4-dihydro-3Hl-2,3-benzoxazine-3-carboxylic acid methyl, propyl and butyl esters can be prepared in the same manner by substituting methyl, propyl and butyl hydroxycarbamates for the ethyl hydroxycarbamate and the correspond ing alcohols for ethanol in the above procedure.

B. l,4-Dihydro-3H-2,3-benzoxazine hydrochloride A solution of 47.25 g. (0.228 mole) of l,4-dihydro-3Hl-2,3- benzoxazine-3-carboxylic acid ethyl ester in 480 ml. of methanol, 190 ml. of water, and 190 ml. of concentrated hydrochloric acid was refluxed for 19 hrs. and evaporated to dryness under reduced pressure. The crystalline residue was washed thoroughly with ether, affording 33.1 g. (85 percent), m.p. 18l-l 84 C. of 1,4-dihydro-3H-2,3-benzoxazine hydrochloride.

C. l,4-Dihydro-3l-l-2,3-benzoxazine An aqueous solution of 5.0 g. of l,4-dihydro-3Il-2,3- benzoxazine hydrochloride was basified with sodium hydroxide, diluted with a saturated sodium chloride solution and extracted with ether to yield an ethereal solution of 1,4-dihydro- 3I'l-2,3-benzoxazine. This compound was isolated by evaporating the ethereal solution to dryness.

I). N-Methyl-l ,4-dihydro-3H-2,3-ben2'oxazine-3-carboxamide An ethereal solution of l,4-dihydlro-3H-2,3-ben2oxazine, prepared as in part C, was dried over a potassium carbonate' magnesium sulfate mixture, treated with 5 ml. of methyl iso' cyanate, and allowed to stand overnight at room temperature. The solid present was collected, washed with a little ether and dried, affording 1.89 g., m.p. 108.5-l09 C., of N-methyllA- dihydro-3l-ll-2,3-benzoxazine-3-carboxamide. Crystallization of the ethereal filtrate residue from a mixture of acetone and cyclohexane afforded crops of 3.2 g., m.p. 108l08.5 C. and 0.2 g., m.p. l07108.5 C. of additional product. Recrystallization of these solids from a mixture of acetonecyclohexane afforded 4.93 g., m.p. 107-l07.5 C., of analytically pure N methyl-1,4-dihydro-3lH-2,3-benzoxazine-3-carboxamide. Spectra (IR, UV, NMR) were consistent with structure.

Anal.

Calcd. for C H N,O,: C, 62.48; H, 6.29; N, 14.58.

N-Ethyll ,4-dihydro-3H-2,3-benzoxazine-3-carboxamide This product was prepared by utilizing substantially the same methods utilized in example 1, except that in step D ethyl isocyanate was substituted for methyl isocyanate. An ethereal solution of free base from 5.0 g. of 1,4-dihydro-3H- 2,3-benzoxazine hydrochloride was treated with 5 ml. of ethyl isocyanate and stored overnight at room temperature. The solution was evaporated to dryness under reduced pressure; recrystallization of the residue from a mixture of acetone and Skellysolve B hexanes afforded crops of 4.14 g., m.p. 75.5-7 6 C., and 0.82 g., m.p. 74.5-75 C. of N-ethyl-1,4-dihydro- 3H-2,3fbenzoxazine-3-carboxamide. A sample recrystallized from a mixture of acetone and cyclohexane for analysis melted at 74.575 C. Spectra (1R, UV, NMR) were consistent with the structure.

Analysis C, 64.06; H, 6.84; N, 13.58. c, 63.68; H, 6.89; N, 13.34.

EXAMPLE 3 3,4-Dihydrol H-2,3-benzoxazine hydrochloride A. 3-Benzoyl-l,4-dihydro-3H-1,B-benzoxazine To a stirred solution of sodium isopropoxide (9.0 g. of 56 percent sodium hydride in mineral oil in 1.0 l. of isopropanol, 0.21 mole) was added a solution of 13.7 g. (0.1 mole) of benzohydroxamic acid in 300 ml. of isopropanol and 17.5 g. (0.1 mole) of ortho-(bis-chloromethyl)benzene in 200 ml. of isopropanol. The reaction mixture was stirred and refluxed for 19 hours and then filtered hot through Celite (infusorial earth). The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in methylene chloride, washed with water, dried over sodium sulfate and concentrated on a steam bath. The methylene chloride was completely displaced with cyclohexane and the hot mixture (some solid present) filtered through infusorial earth. The filtrate was evaporated to dryness, leaving 26 g. of residue which was chromatographed on a column of silica gel (3 l.) with 20 percent acetone in cyclohexane. Fractions of 75 ml. were collected. Essentially homogeneous 3benzoyl-l,4-dihydro-3H- 2,3-benzoxazine was found in fractions 48 through 51. Successive recrystallization of this material from a mixture of methylene chloride and Skellysolve B hexanes, and aqueous methanol, yielded the purified compound; melting point 85-85.5 C. The structure was supported by NMR, IR, and UV spectral data.

Analysis Calcd. for C,,H,,NO,:

C, 75.30; H, 5.48; N, 5.85. C, 75.23; H, 5.79; N, 5.86.

B. 1,4-Dihydro-3H-2,3-benzoxazine hydrochloride 3-Benzoyl-l,4-dihydro-3H-2,3-benzoxazine (2.54 g.) was dissolved in isopropanol (100 ml.) and treated with 25 ml. of 6 N hydrogen chloride in isopropanol. The'solution was refluxed for 2% hrs. and the solvent was evaporated under reduced pressure. The residue was triturated and washed thoroughly with ether, affording 1.50 g. of 1,4-dihydro-3H-2,3-benzoxazine hydrochloride, m.p. 171-174 C. Recrystallization from a methanolethyl acetate mixture afforded 1.45 g. percent) of analytically pure product, m.p. l80.5-l82.5 C. Spectral data (NMR, 1R, UV) supported the structural assignment.

Analysis Calcd. for C,H,NOHC1 C, 55.98; H, 5.87; N, 8.16; Cl, 20.66.

Found: C,56.17;H,6.26;N,8.44;Cl,20.57.

EXAMPLE 4 3-Benzoyl-l ,4-dihydro-3 H-2,3-benzoxazine A solution of 108 g. of benzohydroxamic acid in 788 ml. of 1N sodium hydroxide and 500 ml. of percent ethanol was added to a warm solution of 68.9 g. of ortho-( bischloromethyl)benzene in 1.10 l. of 95 percent ethanol. The clear solution was refluxed overnight and then concentrated to a small volume under reduced pressure, leaving an aqueous suspension of a solid and gum which were separated and washed with water and then thoroughly with ether, leaving 33.8 g. (23 percent of ortho-(bis-benzamidooxymethyl)benzene methyl)benzene (formula V11), m.p. l91.5 C. An analytical sample recrystallized from ethanol melted at l93l93.5 C.

Analysis Calcd. for C,,H,,N,O,:

C, 70.20; H, 5.36; N, 7.44. C, 70.44; H, 5.20; N, 7.27.

EXAMPLE 5 1,6-Dihydro-4-phenyl-2 ,5 ,3-benzodioxazocine Potassium benzohydroxamate (1.75 g., 0.01 mole) was dissolved in 50 ml. of water with vigorous shaking. To this solution was added 30 ml. of ice and 10 ml. of 1N sodium hydroxide. After agitation, the resulting cold solution was added dropwise to a refluxing solution of 1.75 g. (0.01 mole) of ortho-(bis-chloromethyl) benzene in 30 ml. of isopropanol. During the addition two 10-ml. portions of isopropanol were added for clarification of the reaction mixture. After the addition was completed, the reaction mixture was cooled and concentrated under reduced pressure to remove the isopropanol. The aqueous residue was extracted with ether, and the extract was washed with two portions of dilute sodium hydroxide followed by two portions of water, dried over magnesium sulfate and evaporated, leaving 1.90 g. of residue which by thin layer chromatography analysis was found to be a mixture of substantially equal amounts of 3-benzoyl-1,4-dihydro-3H-2,3- benzoxazine and a material of slightly greater mobility on silica gel. This residue was chromatographed on 200 g. of silica gel with 10 percent acetone in cyclohexane collecting 40 ml. fractions. Fractions 9-1 1 (0.44 g. total) had the same mobility as the faster moving spot of the crude residue; recrystallization from a mixture of acetone and Skellysolve B hexanes gave 0.29 g., m.p. 104-106 C., of 1,6-dihydro-4-phenyl- 2,5,3- benzodioxazocine. A sample of 1,6-dihydro-4-phenyl-2,5,3- benzodioxazocine recrystallized from methylene chlorideisopropanol for analysis, melted lO7-l09 C. Spectra (IR, UV, NMR) were consistent with the structure.

Analysis Calcd. for C,,H,,NO,:

C, 7530; H, 5.48; N, 5.85.

Found: C, 75.45; H, 5.33; N, 5.91.

EXAMPLE 6 l,4-Dihydro-3H-2,3-benzoxazine-3-carboxamide To an aqueous solution of 3.0 g. of l,4-dihydro-3H-2,3- benzoxazine hydrochloride (example 1, part B) was added 3.0 g. of potassium cyanate. The suspension which formed immediately was stirred briefly, and the solid was collected, washed with water and dried, affording 2.92 g. of product, m.p. l73l75 C. Successive recrystallization from aqueous acetone and a mixture of acetone and Skellysolve B hexanes afforded an analytical sample of 1,4-dihydro-3H-2,3-benzoxazine-3-carboxamide, m.p. l76l77.5 C. Spectra (lR, UV, NMR) supported the structure.

Analysis Calcd. for C,,H,.,N,0,C, 60.66; H, 5.66; N, 15.72. Found: C, 60.55; H, 6.04; N, 15683.

EXAMPLE 7 iii carboxamidine hydrochloride solvated with methanol, ethyl acetate and water, and melting at l58l60 C. with previous sintering. A sample was dried at C. to obtain unsolvated l,4-dihydro-3lH-2,3-benzoxazine-3-car'boxamidine hydrochloride.

Analysis Calcd. for C,,H N,0-l:lCL

C, 50.59; H, 5.66; N, 119.66; c1, l6.60. Found: 5035; H, 6.]4; N, 19.94; 01,1628.

The free base is prepared by basifying the hydrochloride with aqueous sodium hydroxide, extracting with methylene chloride, and evaporating the extract to dryness.

lclaim:

l. A compound of the formula wherein R is alkyl of one to four carbon atoms, inclusive, or hydrogen.

2. A compound according to claim l wherein R is hydrogen.

3. A compound according to claim ll wherein R is alkyl of one to four carbon atoms, inclusive.

4. A compound of claim 11 wherein R is methyl.

5. A compound of claim l wherein R is ethyl.

6. A compound of the formula: 

2. A compound according to claim 1 wherein R is hydrogen.
 3. A compound according to claim 1 wherein R is alkyl of one to four carbon atoms, inclusive.
 4. A compound of claim 1 wherein R is methyl.
 5. A compound of claim 1 wherein R is ethyl.
 6. A compound of the formula: 